Publication Abstract from PubMed

Human aldehyde dehydrogenases (ALDH) comprise a family of seventeen homologous enzymes that metabolize different biogenic and exogenic aldehydes. To date, there are relatively few general ALDH inhibitors that can be used to probe the contribution of this class of enzymes to particular metabolic pathways. Here, we report the discovery of a general class of ALDH inhibitors with a common mechanism of action. The combined data from kinetic studies, mass spectrometric measurements and crystallographic analyses demonstrate that these novel inhibitors undergo an enzyme-mediated beta-elimination reaction generating a vinyl-ketone intermediate that covalently modifies the active site cysteine residue present in these enzymes. The studies described here can provide the basis for rational approach to design ALDH isoenzyme-specific inhibitors as research tools and perhaps as drugs, to address diseases, such as cancer, where increased ALDH activity is associated with cellular phenotype.